1,2-diamino compounds, processes for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention provides compounds of the general formula: ##STR1## wherein R 1  is a straight-chained or branched C 1  -C 12  -alkyl radical which can be substituted by phenyl, naphthyl or a C 3  -C 7  -cycloalkyl radical; a straight-chained or branched C 2  -C 6  -alkenyl radical which can be substituted by a C 3  -C 7  -cycloalkyl radical or a phenyl or naphthyl radical; a C 3  -C 7  -cycloalkyl radical or a mono- or bicyclic aromatic radical which is unsubstituted or substituted one or more times, the substituents being C 1  -C 4  -alkyl, C 1  -C 4  -alkoxy, carboxyl or carbethoxy, R 2  and R 3 , which can be the same or different, are straight-chained or branched, saturated or unsaturated C 1  -C 6  -alkyl radicals which are optionally substituted by hydroxyl, C 1  -C 3  -alkoxy or C 1  -C 3  -alkoxy-C 1  -C 3  -alkoxy or, together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring which can contain further heteroatoms and is optionally substituted by a lower alkyl or lower alkoxy radical or by an oxygen atom, A is a valency bond or a straight-chained or branched alkylene radical containing up to 6 and preferably up to 3 carbon atoms, R 4  is a mono- or bicyclic aromatic or heteroaromatic radical which is unsubstituted or substituted one or more times, whereby the substituents are alkyl, C 2  -C 6  -alkenyl, alkoxy, C 2  -C 6  -alkenyloxy, hydroxyalkyl, C 2  -C 6  -alkylenedioxy, hydroxyalkoxy, alkoxyethoxy, alkylamino, dialkylamino, alkoxycarbonylethyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy, carboxyl, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, haloalkyl or cyano, as well as halogen atoms, such as chlorine, bromine or fluorine, X is a valency bond or a straight-chained or branched, saturated or unsaturated hydrocarbon radical containing up to 6 carbon atoms, Y is a valency bond or an oxygen atom and R 5  is a C 3  -C 7  -cycloalkyl radical or a mono- or bicyclic aromatic or heteroaromatic radical which is unsubstituted or substituted one or more times, the substituents being alkyl, alkoxy, C 2  -C 6  -alkenyloxy, aralkoxy, hydroxyl, hydroxyalkoxy, alkoxyalkoxy, alkoxycarbonylalkoxy, C 1  -C 2  -alkenylenedioxy, dialkylamino, alkylthio, alkylsulphinyl, alkyl-sulphonyl, alkylsulphonyloxy, hydroxyalkyl, carboxyl, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl or cyano, as well as halogen atoms, such as chlorine, bromine or fluorine, with the proviso that Y cannot be an oxygen atom when X is a valency bond and that when R 1  is a saturated hydrocarbon radical, X must be a radical with at least 2 carbon atoms; as well as the pharmacologically acceptable salts thereof and the optical isomers thereof. 
     The present invention also provides processes for the preparation of these 1,2-diamino compounds and pharmaceutical compositions containing them.

The present invention is concerned with new 1,2-diamino compounds,processes for the preparation thereof and pharmaceutical compositionscontaining them.

The new 1,2-diamino compounds according to the present invention arecompounds of the general formula: ##STR2## wherein R₁ is astraight-chained or branched C₁ -C₁₂ -alkyl radical which can besubstituted by a phenyl, naphthyl or C₃ -C₇ -cycloalkyl radical, or is astraight-chained or branched C₂ -C₆ -alkenyl radical which can besubstituted by a C₃ -C₇ -cycloalkyl radical or by a phenyl or naphthylradical, or is a C₃ -C₇ -cycloalkyl radical or a mono- or bicyclicaromatic radical which is unsubtituted or substituted one or more times,in which the substituents can be C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, carboxylor carbethoxy, R₂ and R₃, which can be the same or different, arestraight-chained or branched, saturated or unsaturated C₁ -C₆ -alkylradicals which can optionally be substituted by hydroxyl, C₁ -C₃ -alkoxyor C₁ -C₃ -alkoxy-C₁ -C₃ -alkoxy, or together with the nitrogen atom towhich they are attached, form a saturated or unsaturated ring which cancontain further heteroatoms and is optionally substituted by a loweralkyl radical, a lower alkoxy radical or an oxygen atom, A is a valencybond or a straight-chained or branched alkylene radical containing up to6 and preferably up to 3 carbon atoms, R₄ is a mono- or bicyclicaromatic or heteroaromatic radical which is unsubstituted or substitutedone or more times, in which the substituents are alkyl, C₂ -C₆ -alkenyl,alkoxy, C₂ -C₆ -alkenyloxy, hydroxyalkyl, C₂ -C₆ -alkylenedioxy,hydroxyalkoxy, alkoxyalkoxy, alkylamino, dialkylamino,alkoxycarbonylalkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl,alkylsulphonyloxy, carboxyl, alkoxycarbonyl, aminocarbonyl, mono- ordialkylaminocarbonyl, haloalkyl or cyano groups, as well as halogenatoms, such as chlorine, bromine or fluorine, X is a valency bond or astraight-chained or branched, saturated or unsaturated hydrocarbonradical containing up to 6 carbon atoms, Y is a valency bond or anoxygen atom and R₅ is a C₃ -C₇ -cycloalkyl radical or a mono- orbicyclic aromatic or heteroaromatic radical which is unsubstituted orsubstituted one or more times, in which the substituents are alkyl,alkoxy, C₂ -C₆ -alkenyloxy, aralkoxy, hydroxyl, hydroxyalkoxy,alkoxyalkoxy, alkoxycarbonylalkoxy, C₁ -C₂ -alkylenedioxy, dialkylamino,alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy,hydroxyalkyl, carboxyl, alkoxycarbonyl, aminocarbonyl, mono-ordialkylaminocarbonyl or cyano, as well as halogen atoms, such aschlorine, bromine or fluorine, with the proviso that Y is not an oxygenatom when X is a valency bond and when R₁ is a saturated hydrocarbon Xmust be a radical containing at least 2 carbon atoms, and thepharmacologically acceptable salts thereof.

The C₁ -C₁₂ -alkyl radical R₁ is preferably methyl, ethyl, propyl,isopropyl, isobutyl, isoamyl, isohexyl, n-hexyl, n-octyl or n-dodecyland especially isobutyl, isoamyl or isohexyl. As a rule, the C₃ -C₇-cycloalkyl radical is cyclopentyl or cyclohexyl. When the alkyl radicalis substituted, then the cycloalkylmethyl, benzyl and phenethyl radicalsare preferred. Preferred C₂ -C₆ -alkenyl radicals are allyl, methallyland isopentenyl. A substituted radical can be styryl or cinnamyl. Mono-and bicyclic aromatic radicals R₁, R₄ and R₅ are preferably phenyl,naphthyl, indanyl, indenyl and tetralinyl.

R₂ and R₃ preferably signify methyl, ethyl, propyl, allyl or methallyl.Rings which R₂ and R₃ can form together with the nitrogen atom to whichthey are attached are preferably pyrrolidine or piperidine rings andespecially the pyrrolidine ring. The heteroatoms which the rings cancontain are nitrogen, sulphur and oxygen. These include rings such aspiperazine, morpholine and thiomorpholine. Substituents of theabove-mentioned rings are especially C₁ -C₃ -alkyl and C₁ -C₃ -alkoxyradicals, for example methyl, ethyl, propyl, methoxy, ethoxy andpropoxy. As a rule, the oxygen substituent, together with the carbonatom to which it is attached, represents a carbonyl group. Correspondingrings are, for example, the pyrrolidinone and piperidinone rings.

Heteroaromatic radicals R₄ and R₅ are preferably pyridyl, pyrimidinyl,pyrazinyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, tetrazolyl,thiazolyl, iso-oxazolyl quinolyl, isoquinolyl, benzofuranyl,benzothienyl, benzothiazolyl, indolyl and furanyl and especiallybenzofuranyl, pyridyl, furanyl and thienyl.

The alkyl radicals, alone or in combination with other radicals ofsubstituents R₄ and R₅ of the ring systems contain up to 6 andpreferably up to 4 carbon atoms and are especially methyl radicals. Thesubstitution can be single or multiple.

The compounds of general formula (I) according to the present inventioncan be prepared in known manner in that

(a) a compound of the general formula: ##STR3## in which R₁, R₂ and R₃have the above-given meanings, is reacted with a compound of the generalformula: ##STR4## in which A, X, Y, R₄ and R₅ have the above-givenmeanings; or (b) a compound of the general formula: ##STR5## in whichR₁, R₂ and R₃ have the above-given meanings, is reacted with a compoundof general formula (III); or (c) a compound of the general formula:##STR6## in which R₁, R₂ and R₃ have the above-given meanings and B is ahalogen atom or an alkoxy radical, is subjected to an amide formationreaction with a compound of general formula (III) and the compoundobtained of general formula: ##STR7## in which R₁, R₂, R₃, R₄, R₅, A, Xand Y have the above-given meanings, is reduced with a complex hydrideor diborane.

The reaction of a compound of general formula (II) with a compound ofgeneral formula (III) to give a compound of general formula (I)according to the present invention takes place in known manner in aninert solvent, for example toluene, xylene or dimethylformamide, at atemperature of from 40° C. and the reflux temperature of the solvent inthe presence of an alkaline condensation agent, for example sodiumhydride or sodamide.

The compounds of general formula (II) can be prepared by reacting acompound of the general formula:

    R.sub.1 OH                                                 (VII)

in which R₁ has the above-given meaning, with epichlorohydrin in thepresence of aqueous sodium hydroxide solution and of a phase transfercatalyst, for example tetrabutylammonium bromide, and the compoundobtained of the general formula: ##STR8## in which R₁ has theabove-given meaning, is reacted with an amine of the general formula:

    R.sub.2 --NH--R.sub.3                                      (IX)

in which R₂ and R₃ have the above-given meanings and the compoundobtained of the general formula: ##STR9## in which R₁, R₂ and R₃ havethe above-given meanings, is reacted with thionyl chloride in an inertsolvent to give a compound of general formula (II).

The reaction of a compound of general formula (IV) with a compound ofgeneral formula (III) to give a compound of general formula (I)according to the present invention takes place in an inert solvent, forexample toluene or xylene, at a temperature of from 40° C. to the refluxtemperature of the solvent in the presence of an alkaline condensationagent, for example sodium hydride or sodamide.

The compounds of general formula (IV) can be prepared by reducing acompound of the general formula: ##STR10## in which R₁, R₂ and R₃ havethe above-given meanings and R is an alkyl radical, with a complexhydride, for example lithium aluminum hydride, in an inert solvent inknown manner to give a compound of the general formula: ##STR11## inwhich R₁, R₂ and R₃ have the above-given meanings and reacting this inan inert solvent with thionyl chloride to give a compound of generalformula (IV).

The starting compounds of general formula (XI) can be prepared accordingto the process described in Federal Republic of Germany PatentSpecification No. 28 02 864.

The reaction of a compound of general formula (V) with a compound ofgeneral formula (III) to give a compound of general formula (VI), aswell as the reduction of this compound to a compound of general formula(I) according to the present invention, takes place according toprocesses known from the literature.

The compounds of general formula (V), in which B is a halogen atom, canbe prepared by hydrolysing a compound of general formula (XI) andreacting the compound obtained of the general formula: ##STR12## inwhich R₁, R₂ and R₃ have the above-given meanings, with a halogenationagent, for example thionyl chloride, in an inert solvent.

The compounds of general formula (III) can be prepared in that, withmaintenance of the above-given definitions for A, X, Y, R₄ and R₅

(a) a compound of the general formula:

    R.sub.4 A--NH.sub.2

is reacted with a compound of the general formula:

    R.sub.5 --Y--COCl

and the amide obtained of the general formula:

    R.sub.4 --A--NH--CO--Y--R.sub.5

is reduced with a complex hydride or diborane; or

(β) a compound of the general formula:

    R.sub.4 --A'--CO--Cl

in which A' is an alkyl radical with up to 5 and preferably 1 or 2carbon atoms, is reacted with a compound of the general formula:

    R.sub.5 --Y--X--NH.sub.2

and the amide obtained of the general formula:

    R.sub.4 --A'--CO--NH--X--Y--R.sub.5

is reduced with a complex hydride or diborane; or

(γ) by reductive amination of a carbonyl compound of the generalformula:

    R.sub.5 --Y--X'--CO--Z

in which Z is a hydrogen atom or an alkyl radical and X' is a saturatedor unsaturated, straight-chained or branched alkyl radical, X' alwayshaving one carbon atom less than X, with an amine of the generalformula:

    R.sub.4 ANH.sub.2

or

(δ) by reductive amination of a compound of the general formula:

    R.sub.4 A'--CO--V

in which V is a hydrogen atom or an alkyl radical and A' is a saturatedor unsaturated, straight-chained or branched alkyl radical, A' alwayshaving one carbon atom less than A, with a compound of the generalformula:

    R.sub.5 YX--NH.sub.2

The compounds of general formula (I) according to the present inventionpossess an asymmetric carbon atom. Therefore, the present invention alsoincludes racemates and the optically-active forms of the compounds ofgeneral formula (I) according to the present invention, as well asprocesses for the preparation thereof.

The optically-active compounds can be prepared from their racemicmixtures by known methods via diastereomeric salts. For the racemateresolution there can be used, for example, tartaric acid, malic acid,camphoric acid, camphorsulphonic acid or dibenzoyltartaric acid.

For the conversion of the compounds of general formula (I) into theirpharmacologically acceptable salts, these are reacted, preferably in anorganic solvent, with the equivalent amount of an inorganic or organicacid, for example hydrochloric acid, hydrobromic acid, phosphoric acid,sulphuric acid, acetic acid, salicylic acid, citric acid, benzoic acid,naphthoic acid, o-acetoxybenzoic acid, adipic acid, maleic acid, oxalicacid, fumaric acid or cyclamic acid.

The compounds of general formula (I) according to the present inventionpossess valuable pharmacological properties. They are characterisedespecially by a blood vessel-relaxing action and can, therefore, be usedfor the therapy of heart-circulatory diseases.

The new compounds of general formula (I) according to the presentinvention and the salts thereof can be administered enterally orparenterally in liquid or solid form. As injection medium it ispreferred to use water which contains the additives usual in the case ofinjection solutions, such as stabilising agents, solubilising agents orbuffers. Such additives include, for example, tartrate and citratebuffers, ethanol, complex formers (such as ethylenediamine-tetraaceticacid and its non-toxic salts) and high molecular weight polymers (suchas liquid polyethylene oxide) for viscosity regulation. Solid carriermaterials include, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weightfatty acids (such as stearic acid), gelatine, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats and solid highmolecular weight polymers (such as polyethylene glycols). Compositionssuitable for oral administration can, if desired, contain flavouring andsweetening agents.

Besides the compounds described in the following Examples, the followingcompounds are also especially preferred.

    __________________________________________________________________________     ##STR13##                                                                    R.sub.1     R.sub.2, R.sub.3 R.sub.4    R.sub.5       A X    Y                __________________________________________________________________________     ##STR14##                                                                                 ##STR15##                                                                                      ##STR16##                                                                                ##STR17##    --                                                                              CH.sub.2                                                                           --                ##STR18##                                                                                 ##STR19##                                                                                      ##STR20##                                                                                ##STR21##    --                                                                              CH.sub.2                                                                           --                ##STR22##                                                                                 ##STR23##                                                                                      ##STR24##                                                                                ##STR25##    --                                                                              CH.sub.2                                                                           --                ##STR26##                                                                                 ##STR27##                                                                                      ##STR28##                                                                                ##STR29##    --                                                                              CH.sub.2                                                                           --                ##STR30##                                                                                 ##STR31##                                                                                      ##STR32##                                                                                ##STR33##    --                                                                              CH.sub.2                                                                           --                ##STR34##                                                                                 ##STR35##                                                                                      ##STR36##                                                                                ##STR37##    --                                                                              CH.sub.2                                                                           --                ##STR38##                                                                                 ##STR39##                                                                                      ##STR40##                                                                                ##STR41##    --                                                                              CH.sub.2                                                                           --                ##STR42##                                                                                 ##STR43##                                                                                      ##STR44##                                                                                ##STR45##    --                                                                              CH.sub.2                                                                           --                ##STR46##                                                                                 ##STR47##                                                                                      ##STR48##                                                                                ##STR49##    --                                                                              CH.sub.2                                                                           --                ##STR50##                                                                                 ##STR51##                                                                                      ##STR52##                                                                                ##STR53##    --                                                                              CH.sub.2                                                                           --                ##STR54##                                                                                 ##STR55##                                                                                      ##STR56##                                                                                ##STR57##    --                                                                              CH.sub.2                                                                           --                ##STR58##                                                                                 ##STR59##                                                                                      ##STR60##                                                                                ##STR61##    --                                                                              CH.sub.2                                                                           --                ##STR62##                                                                                 ##STR63##                                                                                      ##STR64##                                                                                ##STR65##    --                                                                              CH.sub.2                                                                           --                ##STR66##                                                                                 ##STR67##                                                                                      ##STR68##                                                                                ##STR69##    --                                                                              CH.sub.2                                                                           --                ##STR70##                                                                                 ##STR71##                                                                                      ##STR72##                                                                                ##STR73##    --                                                                              CH.sub.2                                                                           --                ##STR74##                                                                                 ##STR75##                                                                                      ##STR76##                                                                                ##STR77##    --                                                                              CH.sub.2                                                                           --                ##STR78##                                                                                 ##STR79##                                                                                      ##STR80##                                                                                ##STR81##    --                                                                              CH.sub.2                                                                           --                ##STR82##                                                                                 ##STR83##                                                                                      ##STR84##                                                                                ##STR85##    --                                                                              CH.sub.2                                                                           --               __________________________________________________________________________

The following Examples are given for the purpose of illustrating thepresent invention:

Example 1.2-(N-Pyrrolidino)-3-isobutoxy-N-phenyl-N-(2-phenyl-ethyl-propylamineoxalate.

6.3 g. N-phenyl-N-(2-phenylethyl)-amine, together with 7.7 g.2-chloro-1-isobutoxy-3-(N-pyrrolidino)-propane are dissolved in 50 ml.anhydrous toluene. 5.8 g. Sodium hydride (50% oily suspension) are addedthereto and the mixture is heated under reflux for 2 hours. It is thencooled, the mixture is poured on to water and the organic phase isseparated off. The aqueous phase is extracted again with toluene. Thecombined organic phases are washed with water, dried over anhydroussodium sulphate and evaporated. The residue is purified bychromatography on a silica gel column (elution agent methylenechloride/2% methanol).

The appropriate column fractions are evaporated. The residue isdissolved in ethyl acetate and the solution mixed with a solution ofoxalic acid in ethyl acetate. The precipitate is filtered off and againrecrystallised from ethyl acetate. There are obtained 2.1 g.2-(N-pyrrolidino)-3-isobutoxy-N-phenyl-N-(2-phenylethyl)-propylamineoxalate; m.p. 95°-96° C.

The halo compounds of general formula (II) required as startingmaterials are prepared analogously to2-chloro-1-allyloxy-3-N-pyrrolidinopropane, the preparation of which isdescribed in the following by way of example:

A mixture of 50 g. allyl alcohol, 160 ml. concentrated aqueous sodiumhydroxide solution, 230 g. epichlorohydrin and 2 g. tetrabutylammoniumbromide is stirred for 3 hours at 45° C. The mixture is then dilutedwith water and extracted with ethyl acetate. The organic phase is washedwith water, dried over anhydrous sodium sulphate and evaporated. Theresidue is distilled in a vacuum to give 67 g.3-allyloxy-1,2-epoxypropane; b.p. 78° C./56 mm.Hg. This is dissolved in80 ml. ethanol and mixed dropwise, while stirring, with a solution of 86ml. pyrrolidine in 80 ml. ethanol. After completion of the addition,stirring is continued for 1 hour at 70° C., the mixture is evaporatedand the residue is distilled in a vacuum to give 70 g.2-hydroxy-1-allyloxy-3-N-pyrrolidinopropane; b.p. 75° C./10⁻² mm Hg.

60 g. 2-Hydroxy-1-allyloxy-3-N-pyrrolidinopropane are dissolved in 120ml. dichloroethane and the solution mixed dropwise, while stirring, with26 ml. thionyl chloride. After completion of the addition, stirring iscontinued for 2 hours at 70° C., the mixture is cooled, mixed withwater, the pH value is adjusted with aqueous sodium hydroxide solutionto 10 and the organic phase is separated off. This is dried overanhydrous sodium sulphate and evaporated. The residue is purified bycolumn chromatography to give 44 g.2-chloro-1-allyloxy-3-N-pyrrolidinopropane as an oily product.

The following compounds are prepared in an analogous way:

      ##STR86##      No. R.sub.1 R.sub.2, R.sub.3 R.sub.4 R.sub.5 A X Y                2 (CH.sub.3).sub.2CHCH.sub.2      ##STR87##      ##STR88##      ##STR89##      -- (CH.sub.2).sub.2 -- Oxalate 95-96° C. ethyl acetate  3     (CH.sub.3).sub.2CHCH.sub.2      ##STR90##      ##STR91##      ##STR92##      -- (CH.sub.2).sub.2 -- Fumarate 103-104° C. ethyl acetate  4     (CH.sub.3).sub.2CHCH.sub.2      ##STR93##      ##STR94##      ##STR95##      -- (CH.sub.2).sub.2 -- Oxalate 147-148° C. ethyl acetate  5     (CH.sub.3).sub.2CHCH.sub.2      ##STR96##      ##STR97##      ##STR98##      -- (CH.sub.2).sub.2 -- Oxalate 134° C. ethyl acetate      6 (CH.sub.3).sub.2CHCH.sub.2      ##STR99##      ##STR100##      ##STR101##      -- (CH.sub.2).sub.2 O Fumarate 94-96° C. ethyl acetate  7     (CH.sub.3).sub.2CHCH.sub.2      ##STR102##      ##STR103##      ##STR104##      -- (CH.sub.2).sub.2 O Fumarate 134° C. ethyl acetate      8 (CH.sub.3).sub.2CHCH.sub.2      ##STR105##      ##STR106##      ##STR107##      -- (CH.sub.2).sub.3 -- Oxalate 96-97° C. ethyl acetate  9     (CH.sub.3).sub.2CHCH.sub.2      ##STR108##      ##STR109##      ##STR110##      -- (CH.sub.2).sub.3 -- Oxalate 112-113° C. ethyl acetate  10     (CH.sub.3).sub.2CHCH.sub.2      ##STR111##      ##STR112##      ##STR113##      -- (CH.sub.2).sub.2 -- Oxalate 95-96° C. ethyl acetate  11     (CH.sub.3).sub.2CHCH.sub.2      ##STR114##      ##STR115##      ##STR116##      -- (CH.sub.2).sub.2 -- oil m/e 380  12 (CH.sub.3).sub.2CHCH.sub.2      ##STR117##      ##STR118##      ##STR119##      CH.sub.2 (CH.sub.2).sub.2 -- oil m/e 394  13 (CH.sub.3).sub.2CHCH.sub.2      ##STR120##      ##STR121##      ##STR122##      -- (CH.sub.2).sub.2 -- oil m/e 425      14 CH.sub.2CHCH.sub.2     ##STR123##      ##STR124##      ##STR125##      -- CH.sub.2 -- Oxalate 152-153° C. ethyl acetate      15     ##STR126##      ##STR127##      ##STR128##      ##STR129##      -- CH.sub.2 -- Oxalate 159-161° C. Isopropanol      16     ##STR130##      ##STR131##      ##STR132##      ##STR133##      -- CH.sub.2 -- Oxalate 128-130° C. ethyl acetate      17     ##STR134##      ##STR135##      ##STR136##      ##STR137##      -- CH.sub.2 --  Oxalate 152° C. ethyl acetate      18     ##STR138##      ##STR139##      ##STR140##      ##STR141##      -- CH.sub.2 -- oil m/e 407      19     ##STR142##      ##STR143##      ##STR144##      ##STR145##      -- CH.sub.2 -- oil m/e 420      20     ##STR146##      ##STR147##      ##STR148##      ##STR149##      -- CH.sub.2 -- oil m/e 436      21     ##STR150##      ##STR151##      ##STR152##      ##STR153##      -- CH.sub.2 -- 159°  C. ethyl acetate      22     ##STR154##      ##STR155##      ##STR156##      ##STR157##      -- CH.sub.2 -- oil m/e 394      23     ##STR158##      ##STR159##      ##STR160##      ##STR161##      -- CH.sub.2 -- oil m/e 407      24     ##STR162##      ##STR163##      ##STR164##      ##STR165##      -- CH.sub.2 -- Oxalate 125-126° C. ethyl acetate      25     ##STR166##      ##STR167##      ##STR168##      ##STR169##      -- CH.sub.2 -- Oxalate 114-115°  C. ethyl acetate      26     ##STR170##      ##STR171##      ##STR172##      ##STR173##      -- CH.sub.2 -- oil m/e 442      27     ##STR174##      ##STR175##      ##STR176##      ##STR177##      -- CH.sub.2 -- Oxalate 173-174° C. ethyl acetate      28     ##STR178##      ##STR179##      ##STR180##      ##STR181##      -- CH.sub.2 -- Oxalate 192-193° C. ethyl acetate      29     ##STR182##      ##STR183##      ##STR184##      ##STR185##      -- CH.sub.2 -- oil m/e 424      30     ##STR186##      ##STR187##      ##STR188##      ##STR189##      -- CH.sub.2 -- oil m/e 408      31     ##STR190##      ##STR191##      ##STR192##      ##STR193##      -- CH.sub.2 -- Oxalate 135-136° C. Isopropanol      32     ##STR194##      ##STR195##      ##STR196##      ##STR197##      -- CH.sub.2 -- oil m/e 426      33     ##STR198##      ##STR199##      ##STR200##      ##STR201##      -- CH.sub.2 -- oil m/e 411       34     ##STR202##      ##STR203##      ##STR204##      ##STR205##      -- CH.sub.2 -- Oxalate 128-130° C. ethyl acetate      35     ##STR206##      ##STR207##      ##STR208##      ##STR209##      -- CH.sub.2 -- oil m/e 382      36     ##STR210##      ##STR211##      ##STR212##      ##STR213##      -- CH.sub.2 -- oil m/e 398      37     ##STR214##      ##STR215##      ##STR216##      ##STR217##      -- CH.sub.2 -- oil m/e 408      38     ##STR218##      ##STR219##      ##STR220##      ##STR221##      -- CH.sub.2 -- oil m/e 378      39     ##STR222##      ##STR223##      ##STR224##      ##STR225##      -- CH.sub.2 -- oil m/e 410      40     ##STR226##      ##STR227##      ##STR228##      ##STR229##      -- CH.sub.2 -- oil m/e 436      41     ##STR230##      ##STR231##      ##STR232##      ##STR233##      -- CH.sub.2 -- oil m/e 408      42     ##STR234##      ##STR235##      ##STR236##      ##STR237##      -- CH.sub.2 -- oil m/e 394      43     ##STR238##      ##STR239##      ##STR240##      ##STR241##      -- -- -- oil m/e 390      44     ##STR242##      ##STR243##      ##STR244##      ##STR245##      -- -- -- oil m/e 402      45     ##STR246##      ##STR247##      ##STR248##      ##STR249##      -- CH.sub.2 -- Oxalate 130-131° C. ethyl acetate      46     ##STR250##      ##STR251##      ##STR252##      ##STR253##      -- CH.sub.2 -- Oxalate 135-136°  C. ethyl acetate      47     ##STR254##      ##STR255##      ##STR256##      ##STR257##      -- (CH.sub.2).sub.2 -- Oxalate 79° C. ethyl acetate      48     ##STR258##      ##STR259##      ##STR260##      ##STR261##      -- (CH.sub.2).sub.2 -- Oxalate 125-126° C. ethyl acetate  49      ##STR262##      ##STR263##      ##STR264##      ##STR265##      -- (CH.sub.2).sub.3 -- Fumarate 127° C. ethyl acetate  50      ##STR266##      ##STR267##      ##STR268##      ##STR269##      -- (CH.sub.2).sub.2 O Oxalate 118-119° C. ethyl acetate   51      ##STR270##      ##STR271##      ##STR272##      ##STR273##      -- (CH.sub.2).sub.3 -- Oxalate 130-131° C. ethyl acetate  52      ##STR274##      ##STR275##      ##STR276##      ##STR277##      -- CH.sub.2 -- oil m/e 365      53     ##STR278##      ##STR279##      ##STR280##      ##STR281##      -- CH.sub.2 -- oil m/e 368      54     ##STR282##      ##STR283##      ##STR284##      ##STR285##      -- CH.sub.2 -- oil m/e 424      55     ##STR286##      ##STR287##      ##STR288##      ##STR289##      -- (CH.sub.2).sub.2 O Oxalate 118-120° C.      56     ##STR290##      ##STR291##      ##STR292##      ##STR293##      -- CH.sub.2 -- oil m/e 424      57     ##STR294##      ##STR295##      ##STR296##      ##STR297##      -- (CH.sub.2).sub.2 -- Oxalate 97-98° C. ethyl acetate  58      ##STR298##      ##STR299##      ##STR300##      ##STR301##      -- (CH.sub.2).sub.2 O Oxalate 93-95° C. ethyl acetate  59      ##STR302##      ##STR303##      ##STR304##      ##STR305##      -- (CH.sub.2).sub.3 -- oil m/e 452      60     ##STR306##      ##STR307##      ##STR308##      ##STR309##      -- (CH.sub.2).sub.4 -- Oxalate 92-95° C.      61     ##STR310##      ##STR311##      ##STR312##      ##STR313##      CH.sub.2 CH.sub.2 -- oil m/e 408      62     ##STR314##      ##STR315##      ##STR316##      ##STR317##      CH.sub.2 CH.sub.2 -- oil m/e 413      63     ##STR318##      ##STR319##      ##STR320##      ##STR321##      -- CH.sub.2 -- oil m/e 424      64     ##STR322##      ##STR323##      ##STR324##      ##STR325##      -- CH.sub.2 -- oil m/e 380      65     ##STR326##      ##STR327##      ##STR328##      ##STR329##      -- CH.sub.2 -- oil m/e 378      66     ##STR330##      C.sub.2 H.sub.5C.sub.2      H.sub.5     ##STR331##      ##STR332##      -- CH.sub.2 -- Oxalate 61-63° C. ethyl acetate      67     ##STR333##      ##STR334##      ##STR335##      ##STR336##      -- CH.sub.2 -- Oxalate 149-150° C. ethyl acetate      68     ##STR337##      ##STR338##      ##STR339##      ##STR340##      CH.sub.2 CH.sub.2 -- oil m/e 438      69     ##STR341##      ##STR342##      ##STR343##      ##STR344##      -- CH.sub.2 -- Oxalate 151-152° C. ethyl acetate      70     ##STR345##      ##STR346##      ##STR347##      ##STR348##      -- CH.sub.2 -- oil m/e 378      71 (CH.sub.3).sub.2CHCH.sub.2     ##STR349##      ##STR350##      ##STR351##      --  CHCHCH.sub.2 -- Oxalate 119-120° C. ethyl acetate  72     (CH.sub.3).sub.2CHCH.sub.2      ##STR352##      ##STR353##      ##STR354##      --      ##STR355##      -- oil m/e 380      73     ##STR356##      ##STR357##      ##STR358##      ##STR359##      -- CH.sub.2 -- Oxalate 136-137° C. ethyl acetate      74     ##STR360##      ##STR361##      ##STR362##      ##STR363##      -- CH.sub.2 -- oil m/e 416      75     ##STR364##      ##STR365##      ##STR366##      ##STR367##      -- CH.sub.2 -- oil m/e 421      76     ##STR368##      ##STR369##      ##STR370##      ##STR371##      -- (CH.sub.2).sub.2 -- oil m/e 430  77 (CH.sub.3).sub.2CHCH.sub.2      ##STR372##      ##STR373##      ##STR374##      -- (CH.sub.2).sub.2 -- oil m/e 440  78 (CH.sub.3).sub.2CHCH.sub.2      ##STR375##      ##STR376##      ##STR377##      -- (CH.sub.2).sub.2 O oil m/e 456  79 (CH.sub.3).sub.2CHCH.sub.2      ##STR378##      ##STR379##      ##STR380##      -- (CH.sub.2).sub.4 -- oil m/e 408  80 (CH.sub.3).sub.2CHCH.sub.2      ##STR381##      ##STR382##      ##STR383##      -- CH.sub.2 -- oil m/e 411      81     ##STR384##      ##STR385##      ##STR386##      ##STR387##      -- CH.sub.2 -- Fumarate 137-138° C. ethyl acetate      82     ##STR388##      ##STR389##      ##STR390##      ##STR391##      -- CH.sub.2 -- oil m/e 364      83     ##STR392##      ##STR393##      ##STR394##      ##STR395##      -- CH.sub.2 -- Oxalate 133-135° C. ethyl acetate      84     ##STR396##      ##STR397##      ##STR398##      ##STR399##      -- -- -- Oxalate 105° C. ethyl acetate      85     ##STR400##      ##STR401##      ##STR402##      ##STR403##      -- CH.sub.2 -- Oxalate 118° C. ethyl acetate      86     ##STR404##      ##STR405##      ##STR406##      ##STR407##      -- -- -- Oxalate 120° C. ethyl acetate      87     ##STR408##      ##STR409##      ##STR410##      ##STR411##      -- CH.sub.2 -- Oxalate 108° C. ethyl acetate      88     ##STR412##      ##STR413##      ##STR414##      ##STR415##      -- CH.sub.2 -- Oxalate 99° C. ethyl acetate      89     ##STR416##      ##STR417##      ##STR418##      ##STR419##      -- (CH.sub.2).sub.2 -- Fumarate 105° C. ethyl acetate  90      ##STR420##      ##STR421##      ##STR422##      ##STR423##      -- -- -- Oxalate 104° C. ethyl acetate      91     ##STR424##      ##STR425##      ##STR426##      ##STR427##      -- CH.sub.2 -- oil m/e 408      92     ##STR428##      ##STR429##      ##STR430##      ##STR431##      -- CH.sub.2 -- Fumarate 148° C. ethyl acetate      93     ##STR432##      ##STR433##      ##STR434##      ##STR435##      -- CH.sub.2 -- oil m/e 384      94     ##STR436##      ##STR437##      ##STR438##      ##STR439##      -- -- -- Oxalate 135° C. ethyl acetate      95     ##STR440##      ##STR441##      ##STR442##      ##STR443##      -- CH.sub.2 -- oil m/e 438      96     ##STR444##      ##STR445##      ##STR446##      ##STR447##      -- CH.sub.2 -- oil m/e 438      97     ##STR448##      ##STR449##      ##STR450##      ##STR451##      -- CH.sub.2 -- oil m/e 452      98     ##STR452##      ##STR453##      ##STR454##      ##STR455##      -- CH.sub.2 -- Fumarate 101° C. ethyl acetate      99     ##STR456##      ##STR457##      ##STR458##      ##STR459##      -- CH.sub.2 -- oil m/e 424      100     ##STR460##      ##STR461##      ##STR462##      ##STR463##      -- CH.sub.2 -- oil m/e 408      101     ##STR464##      ##STR465##      ##STR466##      ##STR467##      -- CH.sub.2 -- oil m/e 422      102     ##STR468##      ##STR469##      ##STR470##      ##STR471##      -- CH.sub.2 -- oil m/e 422      103     ##STR472##      ##STR473##      ##STR474##      ##STR475##      -- CH.sub.2 -- Oxalate 128° C. ethyl acetate      104     ##STR476##      ##STR477##      ##STR478##      ##STR479##      -- CH.sub.2 -- Oxalate 103°      C. ethyl acetate

In Vitro Test Results

Rat aorta segments were suspended in an organ bath and connected to aforce pickup, and stretched to 15 mN. The KrebsHenseleit solution in theorgan bath had the following composition:

NaCl=118 mM; KCl=4.7 mM; MgSO₄ =1.2 mM; CaCl₂ =2.5 mM; KH₂ PO₄ =1.2 mM;NaHCO₃ =25 mM; glucose -11 mM.

The aorta segments were left in the bath for 45 minutes to reachequilibrium, and then a stock solution of KCl was added to the organbath to increase the KCl concentration of the nutrient solution in theorgan bath to 40 mM. After the aorta segments had been exposed for 30minutes to the increased potassium concentration, the test substanceswere added at an identical concentration, (10⁻⁶ mol/liter) to the bathsolution. The test substances produced a relaxation effect which variedwith the different test substances, and is reported in Table 1 below asa percent of the pre-contraction, determined 25 minutes after the testsubstance addition to the bath solution. The percent relaxation reportedis a measure of the Ca++ antagonistic effect of the respective testsubstances. The higher the percent relaxation value reported in theright-hand column of Table 1, the more active the substance.

                  TABLE 1                                                         ______________________________________                                        % relaxation following pre-contraction with 40 mM K+ ions                     Incubation time: 25 minutes                                                   Concentration of the test compound: 10.sup.-6 M/liter                         Number of tested preparations per substance: n = 4                            Example No.     % relaxation                                                  ______________________________________                                        Bepridil (control)                                                                            51                                                            54              79                                                            56              72                                                            63              67                                                            67              58                                                            69              68                                                            24              71                                                            70              82                                                            34              76                                                            57              69                                                            ______________________________________                                         Bepridil =                                                                    β-[2Methylpropoxy)methyl]-N-phenyl-N-(phenylmethyl)-1-pyrro--            lidineethanamine.                                                        

As will be appreciated from Table 1, the compounds of the presentinvention are cardiovascular agents exhibiting antianginal andantiarrhythemic properties.

The compounds of the present invention may be administered to patientsin a suitable amount, generally in an amount of 50 to 1000 mg per dose.The patient will normally be administered from 1 to 3 doses daily. Thetotal daily dosage to the patient will typically be in the range of 1 to40 mg/kg.

We claim:
 1. Compound of the general formula: ##STR480## wherein R₁ is astraight-chained or branched C₂ -C₆ -alkenyl radical; R₄ is a phenylradical which is unsubstituted or substituted at least once by C₁ -C₆-alkyl, C₂ -C₆ -alkenyl, C₁ -C₃ -alkoxy, C₂ -C₆ -alkenyloxy, hydroxy-C₁-C₆ -alkyl, C₂ -C₆ -alkylenedioxy, hydroxy-C₁ -C₃ -alkoxy, C₁ -C₃alkoxyethoxy, C₁ -C₆ -alkylamino, di(C₁ -C₆ -dialkyl)amino, C₁ -C₃-alkoxycarbonylethyloxy, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulphinyl, C₁-C₆ -alkylsulphonyl, C₁ -C₆ -alkylsulphonyloxy, carboxy, C₁ -C₃alkoxycarbonyl, aminocarbonyl, mono- or di(C₁ -C₆ -alkyl)aminocarbonyl,halo-C₁ -C₆ -alkyl, cyano, or halogen; X is a straight-chained orbranched, saturated or unsaturated aliphatic hyrocarbon radicalcontaining up to 6 carbon atoms; Y is a valency bond or --O--; and R₅ isa phenyl radical which is unsubstituted or substituted at least once byC₁ -C₆ -alkyl, C₁ -C₃ -alkoxy, C₂ -C₆ -alkenyloxy, phenyl-C₁ -C₃-alkoxy, hydroxy, hydroxy-C₁ -C₃ -alkoxy, C₁ -C₃ -alkoxy-C₁ -C₃ -alkoxy,C₁ -C₃ -alkoxycarbonyl-C₁ -C₃ -alkoxy, C₁ -C₂ -alkylenedioxy, di(C₁ -C₆-alkyl)amino, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulphinyl, C₁ -C₆-alkylsulphonyl, C₁ -C₆ -alkylsulphonyloxy, hydroxy-C₁ -C₆ -alkyl,carboxy, C₁ -C₃ -alkoxycarbonyl, aminocarbonyl, mono- or di(C₁ -C₆-alkyl)aminocarbonyl, cyano, or halogen; or a pharmacologicallyacceptable salt thereof.
 2. Compound of claim 1, wherein R₁ is iso-C₃-C₃ -alkenyl.
 3. Compound of claim 1, wherein R₁ is methallyl orisopentenyl.
 4. Compound of claim 1, wherein said compound is2-(N-pyrrolidino)-3-methallyloxy-N-benzyl-N-(3,4-dioxymethylenephenyl)-propylamineor salt or isomer thereof.
 5. Compound of claim 1, wherein said compoundis2-(N-pyrrolidino)-3-methallyloxy-N-phenyl-N-(4-methoxy-benzyl)propylamineor salt or isomer thereof.
 6. Compound of claim 1, wherein said compoundis2-(N-pyrrolidino)-3-methallyloxy-N-(3-methoxy-phenyl)-N-(4-methoxy-benzyl)-propylamineor salt or isomer thereof.
 7. Compound of claim 1, wherein said compoundis2-(N-pyrrolidino)-3-methallyloxy-N-(4-methoxy-phenyl)-N-(4-methoxy-benzyl)-propylamineor salt or isomer thereof.
 8. Compound of claim 1, wherein said compoundis 2-(N-pyrrolidino)-3-isopentenyloxy-N-phenyl-N-benzyl-propylamine orsalt or isomer thereof.
 9. A pharmaceutical composition suitable for thetreatment of heart circulatory diseases comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 10. A method of producing a blood vessel relaxingeffect in a patient in need of such effect, comprising administering tosaid patient a blood vessel relaxing amount of a compound of claim 1.11. Method of claim 10, wherein said amount is 50 to 1000 mg per dose,administered 1 to 3 times a day.